Immune Responses in Chronic Diseases May Be Driven by Tissue Stiffness


Stiffness in our tissues causes tension in our cells. Research from the Buck Institute, the University Health Network (University of Toronto), Stanford University, and the University of Alberta shows that stiffness impacts the innate immune system by upping its metabolism. The findings suggest the cellular tension likely sets off an inflammatory loop that contributes to the development of chronic diseases of aging.  Publishing in Cell Reports, and colleagues present an emerging way of looking at how the immune system functions, possibilities for new immune therapeutics, and a call for scientists to reconsider the way they do research.

While stiffness is a recognized factor in acute infections, Winer is particularly focused on how stiffness that arises from the environment impacts immune cells. “While viruses and bacteria are key players in triggering an immune response, we think that the forces in the environment around the cells are an extremely important part of the puzzle that influences immunity,” said Winer. “This work provides support for a new way of thinking about how the immune system functions, suggesting that mechanical force primes and likely controls immunology during acute and chronic disease because it readies the immune system in the face of danger.”

Winer and his team, led by Mainak Chakraborty, Research Assistant at the University Health Network in Toronto and Sue Tsai, a former post-doctoral fellow in the lab, now an Assistant Professor at the University of Alberta, cultured dendritic cells, a component of the innate immune system that orchestrates an immune response, from mouse bone marrow and spleen at different degrees of physiological stiffness.  “DCs grown at physiological resting stiffness showed reduced proliferation, activation and cytokine production compared to cells grown under high stiffness which mimicked fibro-inflammatory disease,” said Chakraborty. “High stiffness grown DCs showed increased activation and flux in major glucose metabolic pathways,” added Tsai.  The findings were not limited to mouse DCs, as human DCs also showed enhanced markers of activity under higher tension.

Researchers identified the Hippo-signaling molecule, TAZ, as an important factor impacting DC metabolism and function under tension in the innate immune response.  Winer says that finding is significant, given that a lab at the University of California, Los Angeles recently showed that same pathway facilitated the effects of tension in the adaptive immune system. “This seems to be a critical pathway for sensing environmental force in both arms of the immune system,” said Winer.

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Journal of Infectious Diseases and Diagnosis